SUMMARY The decline in malaria incidence has stalled globally and incidence is increasing in some high transmission settings of sub-Saharan Africa, including Malawi. The situation is worsening despite the scale up of previously effective interventions, raising concerns that the impact of current malaria control and prevention strategies may be compromised. There is an urgent need for innovative approaches to malaria control and Malawi is currently positioned to assess two of the most promising new interventions. Within the next year, the Malawi Ministry of Health will launch large scale demonstration projects to evaluate a new formulation of insecticide-treated bed nets with a chemical synergist, piperonyl butoxide (PBO), designed to enhance the insecticidal effect of pyrethroids and the new malaria vaccine RTS,S/ ASO1 (RTS,S). In an effort to gain the most information from these pilot studies, Malawi's National Malaria Control Programme (NMCP) have invited the Malawi International Center for Excellence in Malaria Research (ICEMR) to evaluate the effectiveness of the two interventions (alone and in combination) on malaria transmission. In the proposed implementation study, we will assess the impact of PBO nets and RTS,S vaccine on Plasmodium infection prevalence and transmission, the effect of PBO nets on the intensity of pyrethroid insecticide resistance in Anopheles vectors, and the feasibility and cost effectiveness of implementing PBO nets and malaria vaccine when introduced alone or in combination. To address these aims, we will conduct longitudinal studies to assess the impact of vaccination and PBO nets on malaria infection and transmission. Mosquito populations from these same study sites will be analyzed for phenotypic, biochemical, and genotypic evidence of pyrethroid resistance, and the results from areas in which PBO nets have been distributed will be compared to the areas in which conventional nets have been distributed. Selected participants from the longitudinal will participate in interviews and focus group discussions to determine how PBO nets and RTS,S vaccination impact attitudes towards each other and other malaria control interventions. Finally, using the information we and the Ministry of Health collects, we will take advantage of the opportunity created by the pilot studies to conduct a cost-effectiveness analysis of PBO nets and malaria vaccination deployed alone or in combination. The overall goal of our ICEMR is to examine the epidemiological, entomological and behavioral impact of RTS,S vaccine and PBO nets on malaria control and elimination efforts in Malawi. This is essential information that will not otherwise be gathered and provides evidence to guide implementation of these programs in the future.